According to recent publications the morphine metabolite Morphine-6-xcex2-D-glucuronide (M6G) [6] is a more effective and longer lasting analgesic drug than Morphine [5] with fewer side effects1 and, therefore, there is much interest in using M6G, rather than Morphine, as a pain killing drug.2
The traditional approach to glycosylation of 4,5-Epoxymorphinan-6-ols explores Bromoglucuronides as glycoside donor and the Koenings-Knorr procedure for the activation of Bromoglucuronides (Berrang, B., et al., Synthesis, 1997, p. 1165 and references cited therein).
Another approach (Scheinmann, F. et. al., U.S. Pat. No. 5,621,087, see claim 1, 2, 5 and 6, abstract, examples, column 4, line 25-line 45) explores the use of Lewis acids (of the type BF3 and TMSOTf) rather than heavy metals based Lewis acids (March, J., xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4-th edition, A Whiley-Interscience publicaiton, pp. 260-3) for the activation of Bromoglucuronides.
Unfortunately, we did not succeed to obtain 4,5-Epoxymorphinan-6-oxyglucuronide from Bromoglucuronides using activators proposed in U.S. Pat. No. 5,621,087 and did not find such examples in the literature.
Unexpectedly we found that the O-glycosylation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides was accelerated by Zinc containing compounds to give 4,5-Epoxymorphinan-6-oxyglucuronides of formula [1] with high yield. 
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R1 are alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl,
R2 is alkyl, haloalkyl or aralkyl;
R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl or hydrogen;
R4 is alkyl, haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl.
We also found that the xcex1 and xcex2 anomeric selectivity of the conjugation product can be controlled by using different O-protecting groups in aglycon and in Bromoglucuronide as well as by varying the ratio between 4,5-Epoxymorphinan-6-ols and Zinc containing compounds.
It is important to note that only the xcex2-anomer of 4,5-Epoxymorphinan-6-oxyglucuronides was obtained according to Koenings-Knorr procedure and U.S. Pat. No. 5,621,087 procedure (but with other than a Bromoglucuronide glycoside donor).
All of the previously disclosed methods have serious drawbacks for producing material to be used as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise a synthetic procedure without using commercially inaccessible and expensive reagents, and which cleanly produces the desired 4,5-Epoxymorphinan-6-oxyglucuronides, avoiding tedious and expensive purification steps.
The present invention provides a commercially acceptable process for conjugation of 4,5-Epoxymorphinan-6-ols of formula [3] with Bromoglucuronides of formula [2] in the presence of Zinc containing compounds under conditions capable of forming 4,5-Epoxymorphinan-6-oxyglucuronides [1]. 
wherein
position 7 and 8 can be olefin as shown or dihydro adduct;
R1, R2, R3, and R4, are as defined above.
This novel approach was used for the preparation of the known analgesic agent Morphine-6-xcex2-glucuronide [4] and of its xcex1-anomer. 
Other features and advantages will be apparent from the specification and claims.
The present invention is related to a novel process for conjugation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides.
Particularly, the present invention relates to the use of Zinc containing compounds for the activation of Bromoglucuronides in the O-glycosylation reaction of 4,5-Epoxymorphinan-6-ols.
This novel approach has the following advantages:
Zinc containing compounds as activating reagents of Bromoglucuronides are inexpensive and commercially available.
Use of different O-protecting, groups in the aglycon and in the Bromoglucuronide as well as different ratio of 4,5-Epoxymorphinan-6-ols and Zinc containing compounds enable to obtain high anomeric selectivity and produce at will with a high degree of preference either the xcex1 or the xcex2 anomer.
Although any 4,5-Epoxymorphinan-6-ols are suitable for this O-glycosylation, preferably, compounds of formula [3] are used 
wherein
position 7 and 8 can be olefin as shown or dihydro adduct;
R3 and R4 are as previously defined.
More preferably, said 4,5-Epoxymorphinan-6-ols are selected from 3-O-Acylmorphine, 3-O-Acylnormorphine, 3-O-Acylnalbuphine, 3-O-Acylnalorphine, 3-O-Acyldihydromorphine, 3-O-Benzylmorphine, 3-O-Benzyldihydromorphine, N,O3-Dibenzylnormorphine, Codeine, Ethylmorphine, Dihydrocodeine, Pholcodine, 3-O-Alkoxycarbonylmorphine, 3-O-Benzyloxycarbonylmorphine, N,O3-Bis(benzyloxycarbonyl)normorphine.
Although any Bromoglucuronide may be used, it is preferred that compounds of formula [2] are used. 
wherein
R1 and R2 are as previously defined.
More preferably the Bromoglucuronides of the present invention are selected from the compounds of formula [2a]. 
wherein
R are acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R2 is as previously defined.
Most preferably Bromoglucuronides of formula [2b] are used. 
wherein
R are as previously defined.
Although any Zinc containing compound suitable as activating reagents for this O-glycosylation can be used, preferably, Zinc Bromide is used.
It is preferred that about 0.01 equivalents to about 4 equivalents and especially preferred that about 0.5 equivalents to about 2 equivalents of Zinc containing compound is used.
Preferably about 1 equivalent to about 2 equivalents of the Bromoglucuronide [2] is used. It is specially preferred that about 1 equivalent to about 1.5 equivalents of Bromoglucuronide [2] is used. The said 4,5-Epoxymorphinan-6-ol [3] may be used as an individual compound or alternatively as corresponding salts thereof or complexes. Especially preferred is the use of said Zinc containing salt or complexes of [3] without using additional Zinc containing compounds as promoter for said coupling. It is preferred that the said complexes may be prepared in situ.
It may be also preferred to conduct the said Zinc activated O-glycosylation in the presence of additives to buffer or to promote the said Zinc containing compounds. The above additives may be selected from molecular sieves, tertiary amines, tetraalkylureas, organic and inorganic acids and salts.
Any reaction-inert solvent may be used. As used above and elsewhere herein, the expression xe2x80x9creaction-inert solventxe2x80x9d refers to a solvent which does not react or decompose with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. In general, the solvent can comprise a single entity, or contain multiple components. Preferably the sovent is a non-protic reaction inert solvent and it is especially preferred that the solvent is Dichloromethane because of the exellent stereoselectivity it provides. Another solvent may be Chloroform or Dichloroethane.
Any environment or conditions (e.g. temperature, time, solvent) suitable for (i.e., capable of) forming the desired 4,5-Epoxymorphinane-6-oxyglucuronides may be used. However, it is preferred that the reaction occurs at a temperature of about xe2x88x9220xc2x0 C. to about 100xc2x0 C. and preferably from about 40xc2x0 C. to 65xc2x0 C. Below about xe2x88x9220xc2x0 C. the reaction can be slow and above about 100xc2x0 C. undesired side reactions (e.g. anomerisation) can occur. This reaction is conveniently carried out at about 0.5 to about 3 atmospheres, however, the high pressures are espesially preferred for the said coupling.
The present invention could be used as a general method to produce a large number of new compounds. As a result of the said coupling also the salts and complexes of 4,5-epoxymorphinan-6-oxyglucuronides [1] could be obtained in a convenient way.
This invention makes a significant advance in the field of 4,5-Epoxymorphinan-6-oxyglucosides by providing efficient methods of preparing both anomers of 4,5-Epoxymorphinan-6-oxyglucuronides. The deprotected end products are useful as analgesic agents.
It should be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of this novel concept as defined by the following claims.